Abstract Vascular smooth muscle cells (SMC) play a key role in the progression of major vascular diseases including Marfan syndrome (MFS), which is a genetic disorder caused by a mutation in the FBN1 gene that occurs in 1 in 5000 people [1]. MFS can lead to thoracic aortic aneurysm (TAA) that is life threatening [2]. SMC display unique plasticity in switching between a contractile phenotype and a synthetic proliferative phenotype, allowing them to regulate the vessel tone and blood pressure. In addition, SMC function is closely linked with TGFOB signaling, which is a major pathway involved in MFS. Thus, understanding the role of SMC in MFS would be a fruitful approach to develop effective therapeutic strategies for MFS. However, it is often difficult because SMC have limited proliferative capacity and acquire senescence rapidly in culture [5]. Leveraging on access to peripheral blood mononuclear cells (PBMC) from multiple MFS patients at the NHLBI Biologic Specimen and Data Repository, we propose to transdifferentiate endothelial progenitor cells (EPC) isolated from PBMC into induced SMC (iSMC) for disease modeling of MFS. The objectives of this project are (i) to establish a robust system to generate iSMC from the PBMC of MFS patient, and (ii) to fabricate endothelialized iSMC-based tissue-engineered blood vessels (TEBViSMC) that can recapitulate the pathophysiology of MFS blood vessels. We will assess the vasoactive function in response to MFS-related drugs under perfusion. We will also evaluate the epigenetic stability of iSMC to understand the potential impact of cell origin and donor-dependent genetic variants on the fidelity of the vascular disease model system. If successful, this patient-specific in vitro vascular model can help study MFS, screen for potential drugs, and develop effective therapeutic strategies for MFS.